This application is a 371 of PCT/JP00/03169 filed May 17, 2000.
The present invention relates to novel cyanobiphenyl derivatives and more particularly it relates to cyanobiphenyl derivatives or their salts useful as intermediates for biphenylamidine derivatives which are capable of providing selective inhibitors for an activated blood coagulation factor X (hereinafter abbreviated to xe2x80x9cFXaxe2x80x9d) and a process for producing the same.
Thrombin inhibitors have been developed as antithrombotic agents in the past. Since these agents, however, inhibit the thrombin induced platelet aggregation as well as blood coagulation, therefore they have a risk of tendency towards bleeding as a side effect, it is difficult to control the extent of the anticoagulation.
The present inventors, therefore, have conducted intensive studies to find out anticoagulants based on the mode of action other than inhibition of thrombin which has a risk in such side effects. As a result of such effects, the inventors have found that biphenylamidine derivatives have excellent FXa inhibitory activity and can clinically be applied as an anticoagulant (WO99/26918).
Furthermore, the present inventors have continued studies on the biphenylamidine derivatives, then have found out novel compounds useful as intermediates for the biphenylamidine derivatives. The present invention has been accomplished on the basis of these findings.
That is, the present invention is cyanobiphenyl derivatives represented by the following general formula (1): 
[wherein R1 is a hydrogen atom, a C1-C8 alkyl group, an aryl group or an aralkyl group; X is a carboxyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a formyl group, the formula:
xe2x80x94CH2xe2x80x94Y
wherein Y is a chlorine atom, a bromine atom, an iodine atom, an azide group, xe2x80x94OR2 (wherein R2is a hydrogen atom, a C1-C8 alkylsulfonyl group (the C1-C8 alkylsulfonyl group may further be substituted with a halogen atom)), an arylsulfonyl group or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group), or xe2x80x94NHR3 (wherein R3 is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group), the formula: 
{wherein Z1 and Z2 are each independently a chlorine atom, a bromine atom or an iodine atom}, or the formula: 
{wherein R4 and R5 are each independently a hydrogen atom, a C1-C8 alkyl group or a C1-C8 alkylcarbonyl group or both together may form a ring when R4 and R5 are each a C1-C8 alkyl group}], or their salts thereof (hereinafter referred to as the xe2x80x9ccyanobiphenyl derivativesxe2x80x9d).
Further, the present invention is a process for preparing cyanobiphenyl derivatives represented by the following formula (3): 
{wherein R1 is as defined in the formula (2); Y1 is xe2x80x94NHR3 (wherein R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, or their salts, which is carried out a condensation reaction of a compound represented by the following formula (2): 
(wherein R1 is a hydrogen atom, a C1-C8 alkyl group, an aryl group or an aralkyl group), with a compound represented by
Y1xe2x80x94H
{wherein Y1 is xe2x80x94NHR3 (wherein R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, and subsequent a reduction.
In addition, the present invention is a process for preparing cyanobiphenyl derivatives, represented by the following formula (5): 
(wherein R1 is as defined in the formula (4); Y1 is as defined in the above formula (3)), or their salts, by reacting a compound represented by the following formula (4): 
(wherein R1 is a hydrogen atom, a C1-C8 alkyl group, an aryl group or an aralkyl group; Y2 is a chlorine atom, a bromine atom or an iodine atom), with a compound represented by
Y1xe2x80x94H
{wherein Y1 is xe2x80x94NHR3 (wherein R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.
The cyanobiphenyl derivatives of the present invention are represented by the above formula (1), wherein the definitions of substituents in the formula (1) are described as follows.
The xe2x80x9cC1-C8 alkyl groupxe2x80x9d means a straight or a branched carbon chain having 1 to 8 carbon atoms, and include for example methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, isoheptyl group, octyl group, isooctyl group or the like. Among them, one having 1 to 4 carbon atoms is preferable, and methyl group or ethyl group is especially preferable.
The xe2x80x9caryl groupxe2x80x9d means a carbocyclic aromatic group including for example phenyl group or naphthyl group, etc. or a heteroaryl group including for example pyridyl group or furyl group, etc., and phenyl group is preferable.
The xe2x80x9caralkyl groupxe2x80x9d means benzyl group, phenethyl group, phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group or the like, and benzyl group is preferable.
The xe2x80x9cC1-C8 alkoxycarbonyl groupxe2x80x9d means an alkoxycarbonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group or the like. The xe2x80x9cC1-C8 alkoxycarbonyl groupxe2x80x9d is preferably methoxycarbonyl group or ethoxycarbonyl group.
The xe2x80x9caryloxycarbonyl groupxe2x80x9d means phenoxycarbonyl group, naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group, 3-chlorophenoxycarbonyl group, 4-methoxyphenoxycarbonyl group or the like, and phenoxycarbonyl group is preferable.
The xe2x80x9caralkoxycarbonyl groupxe2x80x9d means benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, 3-oxohydroisobenzofuranyloxycarbonyl group or like, and benzyloxycarbonyl group is preferable.
The xe2x80x9cC1-C8 alkylsulfonyl groupxe2x80x9d means a sulfonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes, for example, methylsulfonyl group, ethylsulfonyl group, butylsulfonyl group, hexylsulfonyl group, octylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, heptylsulfonyl group or the like, and methylsulfonyl group is preferable. The alkyl group moiety may further be substituted with a halogen atom, and the xe2x80x9cC1-C8 alkylsulfonyl groupxe2x80x9d includes for example tifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, trichloromethylsulfonyl group, dichloromethylsulfonyl group, monochloromethylsulfonyl group or the like. Trifluoromethylsulfonyl group is preferable.
The xe2x80x9carylsulfonyl groupxe2x80x9d means benzenesulfonyl group, p-toluenesulfonyl group, 4-nitrobenzenesulfonyl group, 1-naphthylsulfonyl group, 8-quinolinesulfonyl group or the like, and p-toluenesulfonyl group is preferable.
The xe2x80x9cC1-C8 alkyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, isoheptyl group, octyl group, isooctyl group or the like. The xe2x80x9cC1-C8 alkyl groupxe2x80x9d is preferably methyl group, ethyl group or isopropyl group.
The xe2x80x9cC1-C8 alkylcarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means a carbonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group, octanoyl group or the like. The xe2x80x9cC1-C8 alkylcarboinyl groupxe2x80x9d is preferably acetyl group.
The xe2x80x9carylcarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means benzoyl group, 4-methoxybenzoyl group or 3-trifluoromethylbenzoyl group and the like or a carbonyl group to which a heteroaryl group is bound such as 2-furylcarbonyl group, 3-pyridylcarbonyl group and the like. The xe2x80x9carylcarbonyl groupxe2x80x9d is preferably benzoyl group.
The xe2x80x9cC1-C8 alkoxycarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means an alkoxycarbonyl group having a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group and the like. The C1-C8 alkoxycarbonyl groupxe2x80x9d is preferably methoxycarbonyl group, ethoxycarbonyl group or tert-butoxycarbonyl group.
The xe2x80x9cC5 -C8 alkoxycarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means an alkoxycarbonyl group having a straight or branched carbon chain having 5 to 8 carbon atoms, and includes for example pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, cyclopentyloxycarbonyl group, hexyloxycarbonyl group, cyclohexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, 2-ethylhexyloxycarbonyl group and the like. The xe2x80x9cC5-C8 alkoxycarbonyl groupxe2x80x9d is preferably pentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group or octyloxycarbonyl group.
The xe2x80x9caryloxycarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means phenoxycarbonyl group, naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group, 3-chlorophenoxycarbonyl group, 4-methoxyphenoxycarbonyl group and the like. The xe2x80x9caryloxycarbonyl groupxe2x80x9d is preferably phenoxycarbonyl group.
The aralkoxycarbonyl groupxe2x80x9d substituted at the nitrogen atom in the 4-piperidinomethyl group means benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonyl group, 3-oxohydroisobenzofuranyloxycarbonyl group and the like. The xe2x80x9caralkoxycarbonyl groupxe2x80x9d is preferably benzyloxycarbonyl group.
The xe2x80x9cC1-C8 alkyl groupxe2x80x9d in R4 and R5 means a straight or a branched carbon chain having 1 to 8 carbon atoms, and includes for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, isoheptyl group, octyl group, isooctyl group and the like. The xe2x80x9cC1-C8 alkyl groupxe2x80x9d is preferably methyl group or ethyl group. In the case wherein R4 and R5 together form a ring, it includes for example ethylene group, propylene group, 2-methylenepropylene group, 2,2-dibromopropylene group and the like, and ethylene group or propylene group is preferable.
The xe2x80x9cC1-C8 alkylcarbonyl groupxe2x80x9d in R4 and R5 means a carbonyl group having a straight-chain or a branched carbon chain having 1 to 8 carbon atoms, and includes for example acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group, octanoyl group and the like. The xe2x80x9cC1-C8 alkylcarbonyl groupxe2x80x9d is preferably acetyl group.
The cyanobiphenyl derivatives of the present invention may form acid addition salts, and may form salts with bases depending on the species of the substituents. These salts are not especially restricted insofar as these salts are pharmaceutically acceptable, and include for example mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate or sulfate, organic sulfonates such as methanesulfonate, 2-hydroxyethanesulfonate or p-toluenesulfonate, organic carboxylates such as acetate, trifluoroacetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate or mandelate, salts with inorganic bases such as sodium salts, potassium salts, magnesium salts, calcium salts or aluminum salts, or salts with organic bases such as methylamine salts, ethylamine salts, lysine salts or ornithine salts.
The preferred range of the cyanobiphenyl derivatives of the present invention is as follows.
In the compounds represented by the above formula (1), cyanobiphenyl derivatives [wherein R1 is a hydrogen atom or a C1-C8 alkyl group in the above definition, and, in the above definition, X is a C1-C8 alkoxycarbonyl group, a formyl group, the formula:
xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is a chlorine atom, a bromine atom, an iodine atom, an azide group, xe2x80x94OR2 (wherein, in the above definition, R2 is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a Cl-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group)) or xe2x80x94NHR3 (wherein R3 is as defined as above)}, the formula: 
{wherein Z1 and Z2 are each as defined above}, or the formula: 
{wherein R4 and R5 are each as defined as above}], or their salts thereof.
The more preferred range is as follows.
In the compounds represented by the above formula (1), the cyanobiphenyl derivatives [wherein R1 is a hydrogen atom or a C1-C8 alkyl in the above definition and, in the above definition, X is a formyl group or the formula:
xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is a chlorine atom, a bromine atom, an iodine atom, xe2x80x94OR2 (wherein, in the above definition, R2 is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group)), or xe2x80x94NHR3 (wherein, in the above definition, R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}], or their salts thereof.
The far more preferred range is as follows:
In the compounds represented by the above formula (1), the cyanobiphenyl derivatives [wherein R1 is a hydrogen atom or a C1-C8 alkyl group in the above definition and, in the above definition, X is a formyl group or the formula:
xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is a chlorine atom, a bromine atom, an iodine atom, xe2x80x94OR2 (wherein, in the above definition, R2 is hydrogen atom, that is, xe2x80x94OR2 is a hydroxyl group), or xe2x80x94NHR3 (wherein, in the above definition, R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a Cl-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}], or their salts thereof.
Examples of the cyanobiphenyl derivatives or their salts of the presence invention are shown in the following table.
Among the compounds listed in the above table, compound Nos. 42, 44, 46, 47, 48, 51, 60, 73, 80, 83, 85, 87, 88, 89, 92, 101, 114 and 121 are preferred, and compound Nos. 42, 44, 46, 47, 51, 60 and 80 are more preferred.
Furthermore, the most preferred range of the cyanobiphenyl derivatives of the present invention is as follows.
Cyanobiphenyl derivatives [wherein, R1 is hydrogen atom or a C1-C8 alkyl group in the above definition, and, in the above definition, X is the formula:
xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is xe2x80x94NHR3 (wherein, in the above definition, R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}], or their salts thereof.
Among the compounds listed in the above table, compound Nos. 47 and 80 are most preferred.
On the other hand, the following cyanobiphenyl derivatives are also within the preferred range of the present invention.
That is, cyanobiphenyl derivatives [wherein, in the above formula (1), R1 is as defined above, and X is, in the above definition, a carboxyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a formyl group, the formula:
xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is a chlorine atom, an iodine atom, xe2x80x94OR2 (wherein, in the above definition, R2 is a C1-C8 alkylsulfonyl group (the C1-C8 alkylsulfonyl group may further be substituted with halogen atoms)), an arylsulfonyl group or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C5-C8 alkoxycarbonyl group or an aryloxycarbonyl group), xe2x80x94NHR3 (wherein, in the above definition, R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C5-C8 alkoxycarbonyl group or an aryloxycarbonyl group)), the formula: 
{wherein Z1 and Z2 are each as defined above}, or the formula: 
{wherein R4 and R5 are each as defined above}], or their salts thereof.
The more preferred range is as follows.
That is, in the above formula (1), R1 is, in the above definition, a hydrogen atom or a C1-C8 alkyl group, and X is, in the above definition, a carboxyl group, a C1-C8 alkoxycarbonyl group, a formyl group, or the formula:
xe2x80x94CH2xe2x80x94Y
{wherein Y is, in the above definition, xe2x80x94OR2 (wherein R2 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C5-C8 alkoxycarbonyl group or an aryloxycarbonyl group)), xe2x80x94NHR3 (R3 is, in the above definition, 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C1-C8 alkoxycarbonyl group or an aryloxycarbonyl group))}, or their salts thereof.
The far more preferred range is as follows.
Cynobiphenyl derivatives [wherein, in the above formula (1), R1 is, in the above definition, a hydrogen atom or a C1-C8 alkyl group, and X is, in the above definition, a formyl group or the formula:
xe2x80x83xe2x80x94CH2xe2x80x94Y
{wherein, in the above definition, Y is xe2x80x94NHR3 (wherein, in the above definition, R3 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C5-C8 alkoxycarbonyl group or an aryloxycarbonyl group))}], or their salts thereof
Among these compounds, the following compounds are especially preferred. Methyl 3-(3-cyanophenyl)-5-formylbenzoate, methyl 3-(3-cyanophenyl)-5-[((N-n-pentyloxycarbonyl)piperidin-4-ylmethyl)aminomethyl]benzoate, methyl 3-(3-cyanophenyl)-5-[((N-n-hexyloxycarbonyl)piperidin-4-ylmethyl]aminomethyl]benzoate, methyl 3-(3-cyanophenyl)-5-[((N-n-heptyloxycarbonyl)piperidin-4-ylmethyl)aminomethyl]benzoate, methyl 3-(3-cyanophenyl)-5-[((N-n-octyloxycarbonyl)piperidin-4-ylmethyl]aminomethyl]benzoate and methyl 3-(3-cyanophenyl)-5-[((N-phenoxycarbonyl)piperidin-4-ylmethyl)aminomethyl]benzoate.
Among the compounds listed above, methyl 3-(3-cyanophenyl)-5-formylbenzoate is further more preferred.
A representative process for synthesizing the cyanobiphenyl derivatives of the present invention is detailed in the following description.
In the present invention, when starting materials or intermediates have substituents which may influence the reaction such as a hydroxyl group, an amino group or a carboxyl group, it is preferable to suitably protect such functional groups to carry out the objective reaction and then eliminate the protecting groups. The protecting group is not especially limited if it is the one which is usually used for each of substituents without adverse effects on other moieties in protecting and deprotecting steps. It includes, for example, a trialkylsilyl group, a C1-C4 alkoxymethyl group, a tetrahydropyranyl group, an acyl group and a C1-C4 alkoxycarbonyl group as a protecting group of a hydroxyl group. It includes, for example, a C1-C4 alkoxycarbonyl group, a benzyloxycarbonyl group and an acyl group as a protecting group of an amino group. It includes, for example, a C1-C4 alkyl group as the protecting group of a carboxyl group. The deprotecting reaction can be carried out according to methods usually conducted for respective protecting groups.
The cyanobiphenyl derivatives of the present invention can be synthesized according to, for example, the following reaction formula (a): 
wherein R1 is as defined in the above formula (1), R6 is a hydrogen atom or a C1-C4 alkyl group and W1 is a chlorine atom, a bromine atom, an iodine atom or a trifluoromethylsulfonyloxy group.
That is, cyanophenylboronic acid derivatives (6) which are precursors are reacted with aryl halides or aryl trifluoromethylsulfonates (7) in the presence of a base and a transition metal catalyst such as palladium or nickel and, if necessary, a phase-transfer catalyst to thereby produce the cyanobiphenyl derivatives of the present invention.
Ethers such as tetrahydrofuran, 1,4-dioxane or dimethoxyethane, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as dichloromethane or chloroform, alcohols such as methanol or ethanol, acetonitrile, dimethylformamide, water or the like or mixed solvents thereof are used as the solvent usually used in this reaction.
Inorganic bases such as potassium carbonate or sodium carbonate, alkoxides such as tert-butoxypotassium and organic tertiary amines such as triethylamine or pyridine are used as the base used in the reaction.
A zerovalent palladium such as tetrakis(triphenylphosphine)palladium, a bivalent palladium such as palladium acetate or diphenylphosphinobutanepalladium dichloride, a bivalent nickel such as [bis(diphenylphosphino)ferrocene]nickel dichloride and the like are used in an amount of 0.001 to 100 mol % as the transition metal catalysts, and tetra-C1-C8 alkylammonium halides or the like in an amount of 0.001 to 100 mol % is used as the phase-transfer catalysts in combination.
Among them, a combination of dimethylformamide as the solvent with potassium carbonate as the base and zerovalent palladium such as tetrakis(triphenylphosphine)palladium as the transition metal catalyst or a combination of water as the solvent, potassium carbonate as the base, palladium acetate as the transition metal catalyst and tetrabutylammonium bromide as the phase-transfer catalyst or a combination of a mixed solvent of toluene-methanol as the solvent, potassium carbonate as the base and palladium acetate as the transition metal catalyst is preferred. The reaction is usually carried out at room temperature or under heating for 0.1 to 100 hours.
When X is represented by xe2x80x94CH2xe2x80x94Y2 described below in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (b): 
wherein R1 is as defined in the above formula (1), and Y2 is a chlorine atom, a bromine atom or an iodine atom.
That is, the cyanobiphenyl derivatives (1a-1) prepared according to the above reaction formula (a) are reacted with halogenating agents in the presence or absence of bases to thereby produce the cyanobiphenyl derivatives (1b) which are the compounds of the present invention.
Ethers such as tetrahydrofuran or diethyl ether, hydrocarbons such as toluene or hexane, halogenated hydrocarbons such as dichloromethane or chloroform or mixed solvents thereof are used as the solvent usually used in the reaction.
Inorganic bases such as potassium carbonate or sodium carbonate or organic tertiary amines such as triethylamine or pyridine are used as the base. Furthermore, phosphorus trihalides, phosphorus pentahalides, thionyl halides and the like are used as the halogenating agents. The reaction is usually carried out at room temperature or under heating for 0.5 to 100 hours.
Among them, a combination of diethyl ether as the solvent with phosphorus tribromide as the halogenating agent is preferred.
When X is represented by xe2x80x94CH2xe2x80x94Y3 described below in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (c): 
wherein R1 is as defined in the above formula (1), and Y3 is xe2x80x94OR2 (wherein R2 may be substituted with a C1-C8 alkylsulfonyl group (the alkyl group may further be substituted with halogen atoms) or an arylsulfonyl group).
That is, the cyanobiphenyl derivatives (1a-1) prepared according to the above reaction formula (a) are reacted with sulfonyl halides or sulfonic acid anhydrides in the presence of bases to thereby produce the cyanobiphenyl derivatives (1c), which are the compounds of the present invention.
Ethers such as tetrahydrofuran or diethyl ether, hydrocarbons such as toluene or hexane, halogenated hydrocarbons such as dichloromethane or chloroform, or mixed solvents thereof are used as the solvent usually used in the reaction.
Sulfonyl halides such as methylsulfonyl chloride, p-toluenesulfonyl chloride and the like and sulfonic acid anhydrides such as methylsulfonic acid anhydride, trifluoromethylsulfonic acid anhydride and the like are used.
Inorganic bases such as potassium carbonate or sodium carbonate or organic tertiary amines such as triethylamine or pyridine are used as the base.
The reaction is usually carried out at room temperature, under cooling with ice or under heating for 0.5 to 100 hours.
When X is represented by xe2x80x94CH2xe2x80x94Y1 described below in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (d): 
wherein R1 is as defined in the formula (1), Y2 and R6 are each as defined in the above reaction formulae (a) and (b), Y4 is xe2x80x94OR2 (wherein R2 is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group, an arylcarbonyl group, a C1-C8 alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group)), and W2 is a bromine atom or a trifluoromethylsulfonyloxy group.
That is, iodobenzene derivatives (8), which are starting materials, are mixed with alcohols represented by Y4xe2x80x94H in the presence of bases to provide ether derivatives (9), which are then monocarbonylated to introduce a substituent group CO2R1. Thereby, benzoic acid derivatives (10) are obtained. Further, a coupling reaction with cyanophenylboronic acid derivatives (6) are carried out to produce cyanobiphenyl derivatives (1d) which are the compounds of the present invention.
The etherification shown in the first step of the reaction formula (d) is carried out by using ethers such as tetrahydrofuran or diethyl ether, hydrocarbons such as benzene or toluene, aprotic polar solvents such as dimethylformamide or hexamethylphosphoric triamide or mixed solvents and the like thereof. Metal oxides such as barium oxide or zinc oxide, metal hydroxides such as sodium hydroxide or potassium hydroxide, metal hydrides such as sodium hydride and the like are used as such a base. The reaction usually proceeds at 0 to 100xc2x0 C. for 3 to 72 hours with stirring. The reaction is preferably carried out at 20 to 80xc2x0 C. for 8 to 36 hours by using sodium hydride in anhydrous ethers such as tetrahydrofuran or diethyl ether.
The reaction for introducing the substituent group CO2R1 shown in the second step of the reaction formula (d) can be carried out by dissolving the ether derivatives (9) obtained in the first step in alcohols represented by R1xe2x80x94OH, adding bivalent palladium catalysts and bases such as tertiary amines, for example, triethylamine and, if necessary, phosphine ligands such as triphenylphosphine and stirring the resulting mixture at room temperature or under heating in an atmosphere of carbon monoxide for 3 to 48 hours to convert the iodine atom into the group CO2R1. The reaction is preferably carried out at 60 to 80xc2x0 C. for 12 to 36 hours by using bistriphenylphosphinepalladium chloride or palladium acetate as the catalyst, diisopropylethylamine or tributylaluminum as the base and methanol as the solvent.
The coupling reaction shown in the third step of the reaction formula (d) is carried out by reacting benzoic acid derivatives (10) with cyanophenylboronic acid derivatives (6) in the presence of transition metal catalysts to thereby produce the cyanobiphenyl derivatives (id) which are the compounds of the present invention.
Ethers such as tetrahydrofuran, 1,4-dioxane or dimethoxyethane, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as dichloromethane or chloroform, alcohols such as methanol or ethanol, acetonitrile, dimethylformamide, water or the like or mixed solvents thereof are used as the solvent usually used in the reaction. Inorganic bases such as potassium carbonate or sodium carbonate, alkoxides such as tert-butoxypotassium or organic tertiary amines such as triethylamine or pyridine are used as such a base. A zerovalent palladium such as tetrakis(triphenylphosphine)palladium, a bivalent palladium such as palladium acetate or diphenylphosphinobutanepalladium dichloride or a bivalent nickel such as [bis(diphenylphosphino)ferrocene]nickel dichloride is used as the transition metal catalyst in an amount of 0.001 to 100 mol %. Furthermore, a tetra-C1-C8 alkylammonium halide or the like is used as a phase-transfer catalyst together in an amount of 0.001 to 100 mol %.
Among them, a combination of dimethylformamide as the solvent, potassium carbonate as the base and a zerovalent palladium such as tetrakis(triphenylphosphine)palladium as the transition metal catalyst, a combination of water as the solvent, potassium carbonate as the base, palladium acetate as the transition metal catalyst and tetrabutylammonium bromide as the phase-transfer catalyst, or a combination of a mixed solvent of toluene-methanol as the solvent, potassium carbonate as the base and palladium acetate as the transition metal catalyst, is preferred. The reaction is usually carried out at room temperature or under heating for 0.1 to 100 hours.
When X is shown by xe2x80x94CH2xe2x80x94Y1 described below in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (e): 
wherein R1 is as defined in the formula (1), and Y1 is as defined in the above formula (3).
That is, the cyanobiphenyl derivatives (1a-2) prepared according to the above reaction formula (a) are mixed with amines represented by Y1xe2x80x94H, if necessary, in the presence of a catalytic amount of acids or dehydrating agents to produce imine intermediates which are subsequently reduced to produce the cyanobiphenyl derivatives (1e) which are the compounds of the present invention.
Ethers such as tetrahydrofuran, 1,4-dioxane or dimethoxyethane, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as dichloromethane or chloroform, alcohols such as methanol or ethanol, aprotic polar solvents such as dimethylformamide, acetonitrile, water and the like, or mixed solvents thereof are used as the solvent usually used in the reaction.
Toluene is preferred for the reaction for preparing the imine intermediates, and methanol is preferred for the subsequent reduction. Metal hydride complex compounds such as sodium borohydride or lithium aluminum hydride are used as the reducing agent. The reduction is also achieved by hydrogenation in the presence of transition metal catalysts such as palladium-carbon, platinum oxide or Raney nickel. Inorganic acids such as hydrochloric acid or sulfuric acid or organic acids such as benzenesulfonic acid or p-toluenesulfonic acid are used as the acid catalysts used in the preparation of the imine intermediates. Molecular sieves 4A, anhydrous sodium sulfate and the like are used as the dehydrating agents.
The reaction is usually carried out at room temperature or under heating for 1 to 100 hours. The reaction for preparing the imine intermediates is preferably carried out at 100 to 200xc2x0 C., and the reduction is preferably carried out at room temperature.
When X is shown by xe2x80x94CH2xe2x80x94Y4 or xe2x80x94CH2xe2x80x94Y1 in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized according to, for example, the following reaction formula (f): 
wherein R1 is as defined in the formula (1), and Y2, Y3, Y4 and Y1 are each as defined in the above reaction formulae (b), (c), (d) and (e).
That is, the cyanobiphenyl derivatives (1b) or (1c) prepared according to the above reaction formula (b) or (c) are mixed with alcohols represented by Y4xe2x80x94H in the presence of bases to thereby synthesize the cyanobiphenyl derivatives (1d) of the present invention. Furthermore, amines represented by Y1xe2x80x94H are mixed therewith in the presence of bases to thereby synthesize the cyanobiphenyl derivatives (1e) of the present invention.
Ethers such as tetrahydrofuran or diethyl ether, hydrocarbons such as toluene or hexane, halogenated hydrocarbons such as dichloromethane or chloroform, aprotic polar solvents such as dimethylformamide, or mixed solvents thereof are used as the solvent usually used in the reaction. Metal hydrides such as sodium hydride, inorganic bases such as potassium carbonate or sodium carbonate or organic tertiary amines such as triethylamine or pyridine are used as such a base. The reaction is usually carried out at room temperature or under heating for 0.5 to 100 hours.
When X is shown by xe2x80x94CH2xe2x80x94N3 in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (g): 
wherein R1 is as defined in the formula (1), Y2 and Y3 are each as defined in the above (b) and (c) and M is an alkali metal atom such as lithium atom, sodium atom or potassium atom or a trialkylsilyl group.
That is, the cyanobiphenyl derivatives (1b) or (1c) prepared according to the above reaction formula (b) or (c) are mixed with azides represented by Mxe2x80x94N3 to thereby synthesize the cyanobiphenyl derivatives (1g) of the present invention.
Aprotic polar solvents such as dimethylformamide or hexamethylphosphoric triamide, ethers such as tetrahydrofuran or diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform or dichloromethane, alcohols such as methanol or ethanol, water, or mixed solvents thereof are used as the solvent usually used in the reaction. Alkali metal azides such as sodium azide or potassium azide, trialkylsilyl azides and the like are used as the azides. A combination of dimethylformamide as the solvent with sodium azide as the azide is preferred.
When X is represented by xe2x80x94CH2xe2x80x94NH2 in the cyanobiphenyl derivatives of the present invention, the cyanobiphenyl derivatives can be synthesized even according to, for example, the following reaction formula (h): 
wherein R1 is as defined as in the formula (1).
That is, the cyanobiphenyl derivatives (1g) prepared according to the above reaction formula (g) are reduced with suitable reducing agents to thereby synthesize the cyanobiphenyl derivatives (1h) of the present invention.
Aprotic polar solvents such as dimethylformamide or hexamethylphosphoric triamide, ethers such as tetrahydrofuran or diethylene glycol dimethyl ether, halogenated hydrocarbons such as chloroform or dichloromethane, alcohols such as methanol or ethanol and water are used as the solvent usually used in the reaction.
Metal hydride complexes such as sodium borohydride or lithium aluminum hydride, metal hydrides such as trialkyltin hydrides, a metal such as zinc or chromium or salts thereof are specifically used as the reducing agent. Otherwise, hydrogenation may be used in the presence of a catalyst such as palladium. A combination of methanol as the solvent with sodium borohydride as the reducing agent is preferred.
The cyanobiphenyl derivatives (1d) or (1e) of the present invention synthesized according to the above reaction formula (a), (d), (e) or () can be converted into the biphenylamidine derivatives described in WO99/26918 by carrying out an amidination as shown in the following reaction formula (i): 
wherein R1 is as defined in the formula (1), Y4 and Y1 are each as defined in the above reaction formulae (d) and (e), R7 is a C1-C4 alkyl group, Y5 is a group in which a nitrogen atom in the 4-piperidinomethyl group is unsubstituted or substituted with a C1-C8 alkyl group or a C1-C8 alkylcarbonyl group or an arylcarbonyl group in the above Y4, Y6 is a group in which a nitrogen atom in the 4-piperidinomethyl group is unsubstituted or substituted with a C1-C8 alkyl group, a C1-C8 alkylcarbonyl group or an arylcarbonyl group in the above Y1, and W3 is a chlorine atom, a bromine atom or an iodine atom.
The amidination is carried out under reaction conditions shown in the following (i-1) or (i-2).
(i-1) Amidination Through Imidate Intermediates Using a Solution of Hydrogen Halides in Alcohols
The reaction is carried out by dissolving the cyanobiphenyl derivatives (1d) or (1e) of the present invention in alcohols represented by R7xe2x80x94OH having 1 to 4 carbon atoms, which contain hydrogen halides represented by, for example, Hxe2x80x94W3 such as hydrogen chloride or hydrogen bromide. The reaction is usually carried out at xe2x88x9220 to +30xc2x0 C. for 12 to 96 hours and is preferably carried out in a solution of hydrogen chloride in methanol or ethanol at xe2x88x9210 to +30xc2x0 C. for 24 to 72 hours.
The reaction of the imidates (11) with ammonia proceeds by stirring the imidates (11) in alcohols having 1 to 4 carbon atoms such as methanol or ethanol, aliphatic ethers such as diethyl ether or halogenated hydrocarbons such as dichloromethane or chloroform or mixed solvents thereof containing the ammonia or amines such as hydroxylamines, hydrazines or carbamic acid esters to synthesize a biphenylamidine derivatives (12). The reaction is usually carried out at xe2x88x9210 to +50xc2x0 C. for 1 to 48 hours and is preferably carried out in methanol or ethanol at 0 to 30xc2x0 C. for 2 to 12 hours.
(i-2) Amnidination Through Imidate Intermediates Prepared by While Directly Bubbling Hydrogen Halides
The reaction proceeds by dissolving the cyanobiphenyl derivatives (1d) or (1e) of the present invention in ethers such as diethyl ether, halogenated hydrocarbons such as chloroform or aprotic solvents such as benzene, adding an equivalent amount or an excess of alcohols represented by R7xe2x80x94OH having 1 to 4 carbon atoms, bubbling hydrogen halides represented by Hxe2x80x94W3 such as hydrogen chloride or hydrogen bromide under stirring at xe2x88x9230 to 0xc2x0 C. for 30 minutes to 6 hours, then stopping the bubbling and more stirring the solution at 0 to 50xc2x0 C. for 3 to 96 hours.
Preferably, the reaction is carried out by bubbling hydrogen chloride at xe2x88x9210 to 0xc2x0 C. for 1 to 3 hours with stirring thereof in halogenated hydrocarbons containing an equivalent amount or an excess of methanol or ethanol and then stirring the solution at 10 to 40xc2x0 C. for 8 to 24 hours without bubbling. The imidates (10) thus obtained can be converted into the biphenylamidine derivatives (12) by carrying out the stirring thereof in alcohols having 1 to 4 carbon atoms such as methanol or ethanol, aliphatic ethers such as diethyl ether or halogenated hydrocarbons such as chloroform or mixed solvents thereof which contain ammonia or amines such as hydroxylamine, hydrazine or carbamic acid esters. The reaction is usually carried out at xe2x88x9220 to +50xc2x0 C. for 1 to 48 hours and is preferably carried out in saturated ethanol solution of ammonia at 0 to 30xc2x0 C. for 2 to 12 hours.
The compounds represented by the above formula (1) can respectively and mutually be synthesized by optional combination of other processes such as known oxidation, reduction, esterification or hydrolysis which are usually adoptable by those skilled in the art.
The cyanobiphenyl derivatives (1) synthesized as described above can be isolated and purified according to known methods, for example, extraction, precipitation, fractional chromatography, fractional crystallization or recrystallization. A salt of the compounds of the present invention can be synthesized by carrying out a usual salt-forming reaction.
The cyanobiphenyl derivatives of the present invention can effectively be used as synthetic intermediates for the biphenylamidine derivatives described in WO99/269 18.